Mental retardation (MR), now known as intellectual disability (ID), is a common developmental disability affecting about 1-3% of the human population. Mental retardation is consistently observed in a significantly large (>70%) number of autism spectrum disorder (ASD) patients. The causation in at least half of all MR is still unknown. Thus the diagnosis and understanding of the molecular mechanisms underlying MR remain limited. It is hypothesized that alterations in a large number of genes, distributed throughout the genome, are major causes of MR. It is increasingly clear that autosomal causes of MR are far more prevalent than X-linked MR. However, very few autosomal MR genes have been identified to date. Thus the identification and functional characterization of autosomal MR genes are a critical prerequisite to understanding the molecular basis of cognitive disabilities. Our long-term goals are to increase the understanding of genes and biological processes involved in brain development and cognitive and behavioral functions, to improve early diagnostic capabilities and ultimately develop strategies for potential curative or ameliorative therapies. The characterization of disease-associated translocation and inversion breakpoints has proven to be a productive strategy to identify genes responsible for MR. The immediate goals of the study are to utilize de novo and familial balanced chromosomal translocations and inversions to identify and characterize three to five autosomal genes involved in brain development and function. Previously, we utilized a positional cloning strategy that involved identifying genes disrupted or altered in translocation/inversion patients and confirming their association with MR by looking for mutations in large cohorts of patients with idiopathic MR. This approach has been used successfully in cloning one X-linked MR gene and seven genes associated with autosomal MR. This strategy, supplemented with an updated streamlined breakpoint mapping approach, array CGH, human genome sequence data, copy number variation data and studies in primary neuronal cells, will be utilized to identify and characterize three to five new autosomal MR genes. The potential role of the novel MR genes in synapse development and plasticity will be also examined. Furthermore, the physiological function of two previously identified MR genes, KIRREL3 and ZBTB20, will be elucidated to define the molecular mechanisms and related pathways underlying MR. The Specific Aims of this proposed research are to: 1) identify autosomal genes associated with chromosome aberrations and establish the identity of the novel MR genes; 2) functionally characterize and evaluate the role(s) for the novel MR genes in neuronal synaptic connectivity; and 3) elucidate molecular mechanisms and pathways underlying two MR genes, KIRREL3 and ZBTB20. Identification and characterization of the genes should provide a major advance in the understanding of brain functions critical for the development of intellectual and adaptive abilities as well as facilitating objective diagnoses in some cases of MR. PUBLIC HEALTH RELEVANCE: The discovery of genes involved in mental retardation will provide immediate benefits for patients and their families by providing improved diagnoses and risk counseling. The understanding of the physiological roles of these genes will provide insight into the molecular mechanisms underlying cognitive disabilities, open up new avenues of investigation into the causes of mental retardation, and may provide possibilities to develop tools for potential curative or ameliorative therapies and thus have the potential to significantly impact public health.